NKT cells are unique T lymphocytes that are known to exert potent immunomodulatory effects, although the mechanisms by which they influence immune responses are not well understood. Unlike most other types of T cells, NKT cells can be functionally activated by self antigens presented by CD1d molecules. This type of autoreactive stimulation is likely to be one of the primary ways that NKT cells are activated in vivo. However, the self antigens recognized by human NKT cells remain poorly characterized, and there is little understanding of the functional consequences of NKT cell autoreactive activation. Based on our preliminary data, we hypothesize that lipid messengers, such as lyso-phospholipids, are auto-antigens for NKT cells, and that this provides a pathway by which NKT cell activation in vivo is directly connected to broader processes of immune regulation. Additionally, we have recently shown that NKT cells induce peripheral blood monocytes to differentiate into immature DCs, and our current data suggests the resulting DCs have distinctive regulatory functions. Hence, we hypothesize that NKT cells influence down-stream immune responses by regulating the differentiation and functional properties of myeloid DCs. Here, we propose: i) to Identify auto-antigens recognized by human NKT cells, and to analyze the molecular requirements for CD1d auto-antigen presentation; ii) to Investigate regulation of NKT cell autoreactivity by physiological lipidmessengers; and iii) to examine the properties of myeloid DC that differentiate in response to NKT cell signals.